Novel 9alpha-fluoro-delta1-corticosteroids and preparation thereof



United States Patent 3,099,654 NOVEL 9a-FLUORO-A -CORTICOSTEROIDS AND PREPARATION THEREOF Robert Joly, Montmorency, Seine-et-Oise, Julien Warnant, Neuilly-sur-Seine, and Bernard Goflinet, Paris, France, assignors, by mesne assignments, to Roussel-UCLAF, S.A., Paris, France, a corporation of France N0 Drawing. Filed July 10, 1961, Ser. No. 122,665 Claims priority, application France Aug. 17, 1960 16 Claims. (Cl. 260-23955) This invention relates to novel l6a-methyl-9u-fluoro- A -corticosterones having the formula CHzOR wherein R is selected from the group consisting of hydrogen, an acyl radical of a mineral acid and an acyl radical of an organic carboxylic acid having 1 to 18 carbon atoms. The invention further relates to a novel process for the preparation of the compounds of Formula I and novel intermediates thereof.

The compounds of Formula I possess a very pronounced anti-inflammatory activity and are useful for the treatment of acute and chronic rheumatic afilictions, radicular pain or sciatic lumbar pains. They are also useful for the treatment of local or generalized inflammatory reactions, infectious dermatitis, asthma, emphysema and fibrosis. They are also useful as intermediates for other steroid compounds.

In copending, commonly-assigned US. patent application Serial No. 124,248, filed May 3, 1961, the preparation of l6u-methyl-A -corticosterone is described. The said compound is an anti-inflammatory agent. The compounds of Formula I which are derived from 16a-methyl- A corticosterone have a higher anti-inflammatory activity than the compounds of the said copending application.

It is an object of the invention to provide novel 16amethyl-9a-fluoro-A corticosterones of Formula I.

It is a further object of the invention to provide a novel process for the preparation of 1604-1116thY1-90c-fl1101'0- A -corticosterones of Formula I.

It is an additional object of the invention to provide novel intermediates for 16oc-methyl-9m-fluoro-A -corticosterones of Formula I.

It is another object of the invention to provide novel anti-inflammatory compositions containing novel 16amethyl-9a-fluoro-A -corticosterones of Formula I.

These and other objects and advantages of the invention will become obvious from the following detailed description.

The compounds of the invention have the formula CHzOR bon atoms.

The acyl radical of the organic carboxylic acid having Patented July 30, 1963 1 to 18 carbon atoms maybe derived from an aliphatic,, aromatic, cycloaliphatic or heterocyclic carboxylic acid. Examples of suitable acids are alkanoic acids such as formic acid, acetic acid, propionic acid, butyric acid, isobutyric acid, valeric acid, isovaleric acid, trimethyl acetic acid, caproic acid, fl-trimethyl propionic acid, heptanoic acid, caprylic acid, pelarginic acid, capric acid, undecylic acid, lauric acid, myristic acid, palmitic acid and stearic acid; alkenoic acids such as undecylenic acid and oleic acid; cycloalkyl carboxylic acids such as cyclopentyl carboxylic acid, cyclopropyl carboxylic acid, cyclobutyl carboxylic acid and cyclohexyl carboxylic acid; cycloalkyl alkanoic acids such as cyclopentyl acetic acid, cyclohexyl acetic acid, cyclopentyl propionic acid and cyclohexyl propionic acid; arylalkanoic acids such as phenyl acetic acid and phenyl propionic acid; aryl carboxylic acids such as benzoic acid and 2,4-dinitrobenzoic acid; phenoxy alkanoic acids such as phenoxy acetic acid, p-chlorophenoxy acetic acid, 2,4-dichlorophenoxy acetic acid, 4-terbutyl-phenoxy acetic acid, 3-phenoxy propionic acid and 4-phenoxy butyric acid; heterocyclic carboxylic acids such as furane-Z-carboxylic acid, 5ter-butylfurane-2-carboxylic acid, 5-br0m0f11rane-2-carboxylic acid and nicotinic acids; B-keto-alkanoic acids, such as acetylacetic acid, p-ropionylacetic acid and butyrylacetic acid; amino acids such as diethylaminoacetic acid and aspartic acid. Examples of other suitable acids are sulfonic acids, phosphoric acid, hydrohalides and sulfuric acid.

The process for the preparation of compounds of Formula I according to the invention comprises dehydrating 2l-acyloxy-l6a-methyl-A -corticosterone wherein the acyl radical is the acyl radical of an organic carboxylic acid having 1 to 18 carbon atoms to form 2l-acyloXy-16amethyl-A -pregnatriene-3,2O dione, simultaneously brominating and formylating the latter to form 21-acyloxy- 9a-bromo-l lfi-formoxy-l6a-methyl-A -pregnadiene-3,20- dione, reacting the latter under weakly alkaline conditions to form 913,1lB-epoXy-l6a-methyl-A -pregnadiene-Zl-ol- 3,20-dione, reacting the said product with an acylating agent to form 21-acyloxy-9 8,1lpi-epoxy-16oc-methyl-A pregnadiene-3,20-dione, reacting the acylated product with hydrofluoric acid to form 21-acyloXy-9u-fluoro-lGet-methyl-A -pregnadiene-llfl-ol-3,20-dione which is saponified to give the free alcohol, 9u-fluoro-16a-methyl-A -corticosterone. To form the acid esters of 9a-fluoro-l6a-methyl- A -corticosterone, the free alcohol is reacted with the corresponding acylating agents such as an acid anhydride or acid chloride in the presence of a tertiary base.

A preferred mode of the process of the invention comprises dehydrating 2l-acetoxy-16a-methyl-N-oorticosterone in the 9,11-position by the action of a sulfonyl halide such as methane sulfonyl chloride or p-toluene sulf-onyl chloride in the presence of pyridine and an N,N-d-i-lower alkyl lower alkanoic acid amide such as dirnethylformamide to form Zl-acetoxy-16a-methyl-A -pregnatri ene-3,20-dione, reacting the latter with N-bromo-succinimide in the presence of dimethylfiormamide and perchloric acid to form 2l-acetoXy-9a-bronro-l lfi-form oky-l6a-methyl-A -pregnadiene-3,ZO-dione, reacting the said bromo product with a weakly alkaline base such as sodium bicarbonate in an inert aqueous organic solvent at reflux temperatures which simultaneously forms the epoxide and saponifies the 21-16St61 to form 913,11B-BPOXY-16oc-II16thYl- A -pregnadiene-ll-ol-i ,20 dione, acyl-ating the latter with acetic anhydride to form 2l-acetoxy-9fi,llj8-epoxy-l6ntmethyl-A -pregnadiene-3,20-dione, reacting the said acylated product with hydrofluoric acid in an organic solvent such as dirnethylformamide .to form 2l-acetoxy-9a-fluoro- 16u-nrethyl-A -pregnadiene-l1fi-ol-3,20-dione, saponifying the latter with aqueous sodium bicarbonate in methanol to form Su-fluoro-l6a-rnethyl-A -corticosterone and 3 recovering the latter. The process of the invention as illustrated in Table I.

TABLE I oHioR, CHZORl now l (3:0 -o= A Lona i LOH: 0=L 0 II III $H20R1 (11112011 HCOO o=0 0:0

I Br 0 i "CH3 I "CH3 CHzOR; (llHiORi 1:0 HO 0:0 1 3 b j "OH; I "CH3 433 VI Ia onion HO 0:0

I i I "CH3 R is an acyl radical of an organic carboxylic acid having 1 to 18 carbon atoms.

The 9a-fluoro-16u-methyl-A -pregnadiene-1 1 8,21-diol- 3,20-dione and its esters are utilized preferably by oral method, by transcu-tanetous method in the form of intramuscular, intraor periarticular injections, or by a local infiltration, and by rectal method.

They can be made in the form of solutions, injectable suspensions prepared with adequate excipients to the principal ingredients and prepared in 'ampoules, multiple dose flacons, in the form of implants, of tablets, of suppositories, of poinades and of creams, and in the form of ophthalmic drops, nasal drops or auricularal drops. The daily dose for an adult is 5 to 30 mg. daily depending on the method of administration.

In the following example there are described several preferred embodiments to illustrate the invention. However, it is to be understood that the invention is not intended to be limited to the specific embodiments.

EXAMPLE Preparation of l 6u-Methyl-9a-Fluaro-A -C0rtic0ster0ne STEP A.PREPARATION OF Zl-ACETOXY-lfia-METHYL- A PREGNATRIENE-3,2O-DIONE. (III) 2 gm. of 2l-acetoxy-l6ot-methyl-A -pregnadiene-115- ol-3,20-dione (II) were dissolved in a mixture of 6 cc. of dimethyliormamide and 2.4 cc. of pyridine. 1.2 cc. of methane sulfonyl chloride were added over a period of thirty minutes to this reaction mixture under agitation in an atmosphere of nitrogen at a temperature of +20 C. The reaction mixture was allowed to stand for a period of two hours at 20 C., then it was poured into 100 cc. of a mixture of water and ice.

The gummy residue was vacuum filtered, washed with water until the wash waters were neutral, and dried. 1.09 gm. of 2l-acetoxy-16a-methy1-A -pregnatriene- 3,20-dione were obtained.

The raw pnoduct was dissolved in alcohol, treated with carbon black, filtered, and the filtrate washed with alcohol. The organic phases were combined and iced for a period of about one hour. The crystals obtained were vacuum filtered, washed with alcohol and dried. Recrystallization was perfiormed from aqueous acetone. The 2l-acetoxy-16 -methyl A -pnegnatriene-3,20 dione (III) had a melting point of 162 C. and a specific rotation [a] =+76.5 (c.=0.5% in acetone).

Analysis.C H O molecular weight=382.48. Calcula ted: C, 75.36%; H, 7.9%. Found: C, 75.5%; H, 7.9%.

This compound is not described in the literature.

The starting compound was prepared according to the process described in United States patent application Serial No. 124,248, filed May 3, 1961, by reacting 16a-methyl- 5,8-pregnane-3a-ol-11,20-dione with bromine in the presence of an enolinaltion agent to form 21-brom0-16umethyI-SB-pregnane-Ba-ol-l1,20-dione, reacting the latter with an alkali metal acetate to form the corresponding 21-acetoxy compound, oxidizing the latter to 21-acetoxy- 16a-m'ethy1-5 8-pregnane-3,11,20-trione, brominatting and dehydrobr-ominating the latter to form 2l-acetoxy-l6amethyl-A -pregnadiene-3,11,20-trione, forming the corresponding 3,20-disemicarbazone, reducing the ll-ketone grouping and hydrolyzing the latter to 21-acetoxy-16mmethy1-A -pregnadiene-1 1 ,8-ol-3,20-dione.

STEP B.PREPARATION OF 21-ACETOXY-9a-BROMO-l1fl- FORMOXY-lGa-METHYL-A -PREGNADIENE-3,2O-DIONE 2.5 gm. of 21-acetoxy-16a-methyl-A -pregnatriene- 3,20-dione (III) were dissolved at 20-25 C. in the absence of light in 25 cc. of dimethylformamide. Then in one single amount 1.395 gm. of Nbromo-succinimide were added under agitation and while bubbling nitrogen therethrough at 20-25 C. A solution of 1.395 cc. of perchloric acid and 3.487 cc. of water was added to the above solution over a period of about five minutes.

A precipitate of ZI-HCBIIOXY-Qoc-bIOIIlO-llfi-fOfIItOXY- 16a-methyl-A -pregnadiene-3,30-dione was formed. The suspension was agitated then for about two hours and thirty minutes, poured into a mixture of 250 cc. of water and ice and agitated for an hour. The precipitate was vacuum filtered, washed with [water until the wash waters were neutral, and dried. 3.15 gm. of 2l-acetoxy-9uhromo-l 1 ,B-formoxy-l6a-melthyl-A pregnadiene 3,20- dione (-IV) were obtained, having a melting point of C. Analysis showed 16.1 oi bromine (theoretical 15.75%). The product was insoluble in water.

The product is not described in the literature.

It was used in the following step of the synthesis Without further purification.

STEP C.-PREPARATION OF 913,11/3-EPOXY-16a-METHYL- A1'4-PREGNADIENE-21-OL-3,2OLDIONE (V) 3 gm. of 21-acetoxy-9a-bromo-11 3-formoxy 16a-methyl-A -pregnadiene-3,20-dione (IV) were placed in suspension at 2 0 C. in 30 cc. of methanol. The suspension was agitated and nitrogen was introduced for a period of about five minutes. Then a solution of 3 gm. of sodium bicarbonate in '30 cc. of water was added. The suspension was heated to reflux under nitrogen and under agitation for a period of about twenty minutes and solution was observed. The reaction mixture was allowed to stand for a period of about forty-five minutes under these conditions, then cooled to +10 C. and 15 cc. of a 10% aqueous acetic acid solution were added in order to bring the pH to 5.5-6. Then 45 cc. of water were added and the mixture was cooled for a. period of one hour at 5 C. The crystal residue was vacuum filtered, washed with water, and dried at 40 C. 1.68 gm. of 9,8,11B-epoxy- 1Gu-methyl-A -pregnadiene-21-ol-3,20-dione (V) were obtained having a melting point of 176-178 C. This product was insoluble in water.

This compound is not described in the literature. STEP D.PREPARATION OF 21-ACETOXY-9fl,11fl-EPOXY- 1Ga-METHYIrA PREGNADIENE-3,2O-DIONE (VI) 1.68 gm. of 9B,l lfi-epoxy-l6a-methyl-A -pregnadiene- 21-ol-3,20-dione (V) were dissolved in 6.72 cc. of pyridine. 3.36 cc. of acetic anhydride were then added under agitation and under nitrogen at 25 C. The reaction mixture was maintained for a period of about three hours under agitation and under nitrogen at 30 C. The reaction mixture was poured into 100 cc. of a mixture of water and ice and the aqueous mixture agitated for a period of one hour and then vacuum filtered. The precipitate was washed with water until the wash waters were neutral and then dried. The raw product was purified by dissolution at elevated temperatures in aqueous dimethylformamide, treatment with carbon black and crystallization in the cold.

1.55 gm. of 21-acetoxy-9,6,l1fi-epoxy-16u-methyl-A pregnadiene-3,I2.0-dione (VI) were obtained having a melting point of 177178 C. and a specific rotation [a] =+79 C.i3 C. (c.=0.5% in chloroform).

The product was soluble in alcohol, acetone, benzene, chloroform, methanol, ethyl acetate and dimethylformamide, insoluble in water and ether.

Analysis.C H O molecular weight=398.48. Calculated: C, 72.33%; H, 7.59%; O, 20.07%. Found: C, 72.1%; H, 7.9%; O, 20.0%.

This compound is not described in the literature. STEP E.PREPARATION OF 21-ACETOXY-9a-FLUORO- 16a-METfiYL-A PREGNADlENE-l1fl-OL-3,20 DIONE (Ill) 1.223 gm. of 21-acetoxy-9B,-11/3-epoxy-l6ot-rnethyl-A pregnadiene-3,20-dione (VI) were introduced into 12.23 cc. of a mixture of dimethylformamide and hydrofluoric acid (ratio 3:4), cooled to -30i2 C. Dissolution was complete in about fifteen minutes. The temperature was then allowed to rise to to +5 C. and the reaction mixture was maintained under these conditions for a period of about two hours.

The solution was poured into a mixture of 61 cc. of ammonia solution and 183 gm. of ice. The mixture was allowed to stand for two hours at 20 C., then the precipitate formed was vacuum filtered, washed with water until the wash waters were neutral, and dried.

The raw product was purified by dissolution at elevated temperatures in alcohol, treatment with carbon black and crystallization in the cold. It can be recrystallized in alcohol. 938 mg. of '21-acetoxy-9m-fluoro-16u-methyl- A -pregnadiene-1'1{3-ol-3,20-d-ione (1b) were obtained, having a melting point of 254 C. and a specific rotation [a] =+'l23i2 (c.=0.5% in chloroform).

The product was soluble in chloroform, soluble in hot acetone, slightly soluble in benzene, insoluble in water, dilute aqueous alhalis and acids and in ether.

Analysis.-C H O F; molecular weight=418.49. Calculated: C, 68.87%; H, 7.46%; F, 4.54%. Found: C, 68.6%; H, 7.4%; F, 4.5%. Ultraviolet spectra=k ethanol 239 my, e=l5,100.

This compound is not described in the literature.

STEP F.-PREPARATION OF 16a-METHYL-9a-FLUORO- A CORTICOSTERONE (Ia) 100 mg. of 21-acetoxy-9a-fluoro-l6a-methyl-A -preg nadiene-llfl-ol-3,20-dione (la) were suspended in a solution of 2.5 cc. of methanol, '50 mg. of sodium bicarbonate and 1.15 cc. of water. Nitrogen was allowed to bubble through the suspension at 20 C. for a period of fifiteen minutes. Then the suspension was raised to reflux under nitrogen for a period of about forty-five minutes. The solution obtained was cooled at 2 0 C. and the pH value was adjusted to 5.5 by the addition of a 25% aqueous acetic acid solution. The methanol was distilled and an oily suspension was obtained. The suspension was cooled for one hour at about 0 C. The crystals obtained were vacuum filtered, washed with water, and dried.

The raw product was obtained with a yield of the order of and was recrystallized from ethyl acetate. 16a-methyl-9a-fiuoro-A corticosterone (Ia) was obtained having a melting point of 217 C., percent fiuorine=5.0% (theoretical: 5.04%). It was soluble in alcohol, acetone and chloroform, soluble in hot ethyl acetate, slightly solu- =b1e in ether and benzene, insoluble in water and dilute aqueous acids and alkalis.

This compound is not described in the literature.

Pharmacodynamic Study of 21 -Acet0xy-9a-Flu0ro-16a- Met/1yZ-A -Pregnadiene-JJ 8-OI-3,20-Di0ne DETERMINATION OF ANTI-INFLAMMATORY ACTIVITY The technique employed was a modification of the cotton gnanuloma test described by Singer (Proc. Soc. Exp. Biol. Med. 92, 23, 1956) by operating on a nonsu-nrenal ectomized rat, as was made by Arth (J.A.C.S. 80, 3161, 1958). In the ventral region, under the pelt of preferably female rats two pellets of cotton of 10 mg. each were implanted. Once in the morning and once in the evening, 21-acetoxy-9u-fluoro416a-methyl-A -pregnadiene-llfi-ol-3,20-dione was administered orally in aqueous suspension for a period of two days. The third day the animals were sacrificed, sixteen hours after the last administration.

The pellets in association with the granuloma tissue were then cut out and weighed after desiccation in the oven. The initial weight of cotton was subtracted to obtain the net weight of granuloma. This was expressed in percent of Weight of gnanuloma in the control animals. The coefficients of activity were determined by graphic analysis of the activity curve=f (log dosage).

The D1 which is the 50% inhibitory dose for the By oral method, 21-acetoxy-9a-fluoro-lGet-methyl- A -pregnadiene-l1;8-ol-3,20-dione had an action 2.4 times superior to that of prednisolone acetate.

The 50% inhibitory dose (D1 was of the order of 1.25 mg. per kg.

TESTS OF ACUTE TOXICITY The tests were made on mice of the Roclcland strain weighing between 1 8 and 22 gm. The product was used in an aqueous suspension in the concentration of 10 mg. per cc.

This suspension was injected subcutaneously in doses of 50 and mg. per kg. in groups of ten mice per dose. The duration of observation after injection was one Week. No sign of intoxication was observed in the several hours which followed the injection. There was noted on the sixth day after injection one death among the mice having received 100 mg. per kg. The compound is thus devoid of toxicity in the dosage of 50 mg. per kg. and the only death occurring tardily with a dose of 100 mg. per kg. could not be attributed with certainty to the product being administered.

Various modifications of the process of the invention may be made without departing from the spirit or scope thereof, and it is to be understood that the invention be limited only as described in the appended claims.

We claim:

1. A compound having the formula i O v wherein R is selected from the group consisting of hydrogen, an acyl radical of a mineral acid and an acyl radical of an organic carboXy-lic acid having 1 to 18 carbon atoms.

2. 16a-methyl-9a-fluoro-A -corticosterone.

3. 21 acetoxy 90c fiuoro 160a methyl A pregnadiene-l 15-ol-3,20 dione.

4. A compound having the formula CHzO R1 CHzO R1 Hiio A I wherein R is an acyl radical of an organic carboxylic acid having '1 to 18 carbon atoms.

7. 21 acetoxy 9a bromo 115 formoxy 16amethyl-A -pregnadiene-3,20-dione.

8. 95,115 epoxy 16cc methyl A pregnadiene- 21-ol-3,20-dione.

9. A compound having the formula wherein R is an acyl radical of an organic carboxylic acid having 1 to 18 carbon atoms.

10. 21 acetoxy 95, 115 epoxy 16oz methyl A pregnadiene-3,20-dione.

CHzOR HOW I (5 0 I ]-CH3 wherein R is selected fr'om the group consisting of hydrogen, an acyl radical of a minenal acid and an lacyl radical of an organic carboxylic acid having 1 to 18 carbon atoms, which comprises dehydrating 21-acyloxy-16umethyl-N-corticosterone wherein the acyl radical is an acyl radical of an organic carboxylic acid having 1 to 18 carbon atoms to form ZI-acyloxy-l6a-methyl-A pregnatriene-3,20-dione, simultaneously brominating land formylating the latter with N-bromosuccinimide in the presence of dimethylforrnamide and perchloric acid to form 21-acyloxy-9a-bromo-1 15-formoxy-l 6u-methy1-A pregnadiene-3,20-dione, reacting said brominated product under weakly alkaline conditions to form 95,115-epoxya methyl-A hpregnadienea1-o1-3,20-dione, acylating the latter to form 2l acyloxy-95,115-epoXy-16a-methyl- A -pregnadiene-3,20'-dione, reacting the lacylated product with hydrofluoric acid to form 21-acyl'oXy-9a-fluoro-16amethyl-A -pregnadiene-l15-ol-3,20 dione and recovering a compound of the above formula.

12. The process of claim 11 wherein the dehydration is effected with a isulfonyl halide selected from the group consisting of alkyl sulfonyl halides and aryl sulfonyl halides in the presence of pyridine and dimethylfonmamide.

13. The process of claim 11 wherein the Weak alkali is sodium bicarbonate.

14. The process of claim 11 wherein the acylation is efiected with acetic anhydride.

15. The process of claim 11 wherein the hydrofluoric acid is in d-iinethylfonm'amide.

16. A process for the preparation of 9oc-fi1lO1'O-16amethyl-A corticosterom which comprises reacting 21- acetoxy-1'6u-methyl-A -corticosterone with methane sulfonyl chloride in the presence of pyridine and dimethylforrnialmide to form 2l-acetoxy-lGa-methyl-A -pregnatriene-3,20dione, reacting the latter with N-bromo-succinimide in the presence of dimethylfonmalmide and perchlonic acid to form 21 acetoXy-9a-bromo-115-formoxy- 1Ga-rnethyl-A pregnadiene-3,ZO-dione, reacting the said brominated product with sodium bicarbonate in an aqueous organic solvent to form 95,115-epoXy-16a-methyl-A pregnadiene-Z1-ol-3,20-dione, reacting the latter with acetic anhydride to form 21-acetoxy-95,115-epoxy-16amethyl-a -pregnadiene-3,ZO-dione, reacting the :acetoxylated product with hydrofluoric acid in dimethylformamide to form 21-acetoXy-9a-fluoro-l6a-methyl-A -pregnadiene-115-ol-3,20-dione, reacting the said fiuoro product with aqueous sodium bicarbonate in methanol to form 9a-fiuoro-l6a-methyl-A -corticosterone and recover the latter.

No references cited.

UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION July so, 1963 Patent No., 3.099.654

Robert Joly et a1 It is hereby certified that error appears in the above numbered paten't requiring correction and that the said Letters Patent should read as corrected below.

Column 4, line 11 for "-16 methyl read floor-methyl column 6, lines 67 to 75, for the upper right-hand portion of the formula reading read 3 Signed and sealed this 25th day of February 1964.

(SEAL) Attest: ERNEST W. SWIDER Edd i H L HEINULUS Ac ting Commissioner of Patents Attesting ()fficer 

9. A COMPOUND HAVING THE FORMULA 